Neonatal White Matter Injury Trial (WRAP)

Official title

An Open-label, Dose-escalation, Phase I/Ib Clinical Trial to Assess the Safety and Pharmacokinetics of Clemastine in Preterm Neonates With White Matter Injury (WRAP)

Overview

The researchers are investigating a new treatment for white matter injury, which is a common type of brain injury in premature babies. The drug, clemastine, is experimental. This means that the drug is not approved by the Food and Drug Administration (FDA) for the treatment of white matter injury. The main purpose of this study is to learn whether clemastine is safe to give to infants with white matter injury. The researchers also want to understand how much clemastine gets into an infant's body when the medication is taken by mouth, and how long it stays in the body.

Detailed description

Preterm white matter injury (WMI) is the most common type of brain injury in premature infants and is associated with adverse neurological outcomes, including motor and cognitive disability and seizures. Preterm WMI involves an arrest of differentiation in the oligodendroglial cell lineage and a failure of normal developmental myelination. No therapies exist that directly promote brain repair and myelination or can be given at the time that preterm WMI has been identified and is likely most amenable to treatment. The lack of available treatments inherently limits the possibility for functional recovery in affected infants. Clemastine is an antihistamine and antimuscarinic agent that was identified in a high-throughput screen of FDA-approved compounds that significantly promote myelination in vitro. Clemastine was subsequently shown to promote myelination and improve functional recovery in multiple animal models of WMI, including preterm WMI, and induces remyelination in adult patients with multiple sclerosis. Clemastine is therefore an ideal potential candidate treatment for preterm WMI. The investigators will be conducting a Phase I/Ib open label dose-escalation and dose expansion study to test the safety and pharmacokinetics of oral clemastine treatment in neonates with preterm WMI.

Interventions

• Drug Clemastine fumarate
  Clemastine fumarate oral suspension

Primary outcome measures

• Number of subjects who experience dose limiting toxicity [Time frame: From study drug administration through 30 days after the last dose]

Secondary outcome measures (7)

• Number of patients who experience any adverse events related to the study drug [Time frame: From study drug administration through 30 days after the last dose]
• Pharmacokinetics of Clemastine in Preterm Neonates [Time frame: From day 1 through day 15]
• Pharmacokinetics of Clemastine in Preterm Neonates [Time frame: From day 1 through day 15]
• Pharmacokinetics of Clemastine in Preterm Neonates [Time frame: From day 1 through day 15]
• Pharmacokinetics of Clemastine in Preterm Neonates [Time frame: From day 1 through day 15]
• Pharmacokinetics of Clemastine in Preterm Neonates [Time frame: From day 1 through day 15]
• Pharmacokinetics of Clemastine in Preterm Neonates [Time frame: From day 1 through day 15]

Eligibility criteria

Inclusion criteria

• Born at ≤32 weeks gestational age based on prenatal ultrasound or last menstrual period (LMP).
• Current age of between 35-41 weeks PMA.
• Imaging evidence of white matter injury on any scan as defined by either brain MRI or cUS criteria:

• Brain MRI with Grade Ib WMI or higher based on the Martinez-Biarge et al 2016 criteria.
• cUS with Grade 3 or higher white matter abnormalities based on Miller et al 2003 criteria.
• Currently hospitalized in a participating intensive care nursery.

Exclusion criteria

• Known or suspected metabolic or chromosomal disorder or major congenital anomalies
• Major intracranial hemorrhage within the last 1 week or intracranial hemorrhage of any age that is not controlled or continuing to cause significant mass effect or midline shift.
• History of cardiac arrhythmia or current ongoing tachycardia with baseline heart rate >10% age expected norms.
• Hypotension requiring ongoing vasopressor or inotropic support.
• Not able to receive enteral medications.
• Clinically significant sedation due to critical illness or medications.
• Concomitant use of any other putative neuroprotective or myelination promoting therapy as determined by the investigator.
• Serum creatinine, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) >2x the upper limit of normal for age.
• Family history of epilepsy due to a confirmed or suspected genetic cause.
• History of confirmed seizure activity.
• If ≥36 weeks postmenstrual age, required respiratory support greater than 2L/min, noninvasive positive airway pressure, or mechanical ventilation upon reaching 36 weeks postmenstrual age due to diagnosis of moderate or severe BPD.
• If less than 36 weeks postmenstrual age, currently requiring respiratory support greater than 2L/min, noninvasive positive airway pressure, or mechanical ventilation, unless respiratory support is being given to promote lung development and not due to clinical need.
• Major medical conditions, laboratory abnormalities, or concurrent treatments that, in opinion of the investigator, may affect interpretation of study results or patient safety.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of California, San Francisco — San Francisco

Identifiers

NCT: NCT07688746 · 26-45933 · 1DP2NS148743-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗